Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers
Name
nihms-1641973.pdf
Description
Accepted version
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6.76 MB
Format
Adobe PDF
Checksum (MD5)
ae6089006ceb14f18651dac5bc8b6def
Author(s)
Mandala, Venkata S
McKay, Matthew J
Shcherbakov, Alexander A
Dregni, Aurelio J
Kolocouris, Antonios
Hong, Mei
Date Issued
2020
Journal
Nature Structural and Molecular Biology
Publisher
Springer Science and Business Media LLC
Citation
Mandala, Venkata S, McKay, Matthew J, Shcherbakov, Alexander A, Dregni, Aurelio J, Kolocouris, Antonios et al. 2020. "Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers." Nature Structural and Molecular Biology, 27 (12).
Version
Author's final manuscript
Abstract
An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E’s transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1038/S41594-020-00536-8
